Review Article Syncytiotrophoblast Functions and Fetal ...malaria on syncytiotrophoblast function is paramount in developing novel interventions for the control of placental pathology

Review ArticleSyncytiotrophoblast Functions and Fetal GrowthRestriction during Placental MalariaUpdates and Implication for Future Interventions

Winifrida B Kidima

Department of Zoology College of Natural and Applied Science University of Dar es Salaam PO Box 35064Dar es Salaam Tanzania

Correspondence should be addressed to Winifrida B Kidima kidimawudsmactz

Received 23 June 2015 Revised 8 September 2015 Accepted 4 October 2015

Academic Editor Louiza Belkacemi

Copyright copy 2015 Winifrida B KidimaThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Syncytiotrophoblast lines the intervillous space of the placenta and plays important roles in fetus growth throughout gestationHowever perturbations at the maternal-fetal interface during placental malaria may possibly alter the physiological functions ofsyncytiotrophoblast and therefore growth and development of the embryo in utero An understanding of the influence of placentalmalaria on syncytiotrophoblast function is paramount in developing novel interventions for the control of placental pathologyassociated with placental malaria In this review we discuss how malaria changes syncytiotrophoblast function as evidenced fromhuman animal and in vitro studies and further how dysregulation of syncytiotrophoblast function may impact fetal growth inutero We also formulate a hypothesis stemming from epidemiological observations that nutrition may override pathogenesisof placental malaria-associated-fetal growth restriction We therefore recommend studies on nutrition-based-interventionalapproaches for high placental malaria-risk women in endemic areas More investigations on the role of nutrition on placentalmalaria pathogenesis are needed

1 Introduction

Plasmodium falciparum is known to cause the most severeform of malaria a disease that claims the lives of about onemillion people annually [1] The disease is severe in childrenunder the age of five and in pregnant women In pregnantwomen malaria is associated with an increased risk of poorpregnancy outcomes including maternal anemia pretermdelivery (PTD) (ie delivery before 37 weeks of gestation)and fetal growth restriction (FGR) which is defined as inabil-ity of the fetus to reach genetically predetermined size andweight at term [2] Anemia PTD and FGR are major causesof malaria-associated low birth weight (LBW) babies Theprevalence of LBW babies as a result of placental malaria hasbeen well documented in malaria endemic areas includingThailand Papua New Guinea and Sub-Saharan Africancountries The overall prevalence of malaria-associated LBWbabies from studies in endemic areas from year 1985 to 2000has been estimated to be 20 of live births (reviewed in [3])

Studies show that infants born with LBW not only haveincreased risks of dying in the first year of life but havepotential health problems in adulthood [4 5] Efforts tounderstand the mechanism of disease pathology that leadsto poor pregnant outcomes are important for identifyingtargets for future intervention(s) and designing approachesthat could lead to disease prevention

Placental malaria changes the environment in the inter-villous space of placenta (Figure 1) It occurs as a result ofP falciparum infected erythrocytes (IE) binding to syncy-tiotrophoblast (ST) a continuous multinucleated special-ized epithelia layer that covers interior of the villous of theplacenta P falciparum-IEs specifically bind on ST receptorsknown as chondroitin sulphate A (CSA) and hyaluronic acid[6ndash9] Binding of IE to ST leads to sequestration of IE inthe intervillous space (IVS) of the placenta The ability ofIE to bind on CSA is conferred by the parasitersquos variantsurface antigen belonging to var gene subfamily (VAR2) thatis expressed on the surface of IE called VAR2CSA [10ndash12]

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 451735 9 pageshttpdxdoiorg1011552015451735

2 BioMed Research International

Maternal tissue

MQ M

Lymphocyte

GP1-anchor

TLR12

DNA

Hemozoin

VAR2CSA

HA

IE

CSA (a)

(b) (c)

E

IVS

Syncytiotrophoblast

Chemokine(s) Cytokine(s)

Cytokine R NALP3 TLR9

Figure 1 The microenvironment in the intervillous space of the placenta during active placental malaria (a) Interaction of parasite ligandVAR2CSA [10 12] with CSA that is expressed by ST [8 13] (b) Recognition of parasite bioactive molecules of schizogony by surface PRRsexpressed by both maternal macrophages and fetal syncytiotrophoblast that is malarial GPI-anchor bind TLR1TLR2 or TLR2TLR6 [14]and parasitersquos DNA is recognized by TLR9 [15] and hemozoin by TLR9 (see [16] and inflammasome (NALP3) [17]) (c) Inflammation in theIVS is attributed to chemokines and cytokines secreted by maternal macrophages monocytes and T cell as well as ST [15 16 18ndash20] (HAhyaluronic acid CSA chondroitin sulphate A IVS intervillous space NALP3 inflammasome GPI glycosylphosphatidylinositol IE infectederythrocyte E erythrocyte)

Generally sequestration of IE in the IVS leads to secretion ofchemokines resulting in inflammatory cells recruitment andcytokine productionwhich is associatedwith poor pregnancyoutcomes [18 21 22] Although placental malaria is largelyasymptomatic there is a correlation between peripheral andplacental parasitemia at delivery Placental malaria can becategorized as acute chronic or previous infection usingspecific pathological criteria [23] While chronic placentalmalaria has been associated with an increased risk of FGRacute placental malaria has been associated with PTD inmalaria endemic areas [24] However the major questions todate are the mechanisms on how chronic placental malariainduces FGR and PTD In this review we discuss selectedfunctions of ST and then highlight the role of malaria indysregulation of these functions using evidence from animalhuman and in vitro studies We then develop a modelthat describes the relationship between placental malariaFGR and the dysregulated syncytiotrophoblast function Wesuggest a potential interventional approach targeting STusing evidence from epidemiological studies

2 The Placenta and Its Response to Malaria

21 Maternal Responses to Malaria and Effect on the PlacentaAlthough pathogenesis of placental malaria is not completely

understood the IE binding to ST and recognition of parasiteby maternal macrophages induce secretion of chemokinesthat recruit maternal monocytes into the IVS resulting ininflammation Studies show that there is high level of mono-cytes and macrophages in the IVS of the placenta duringactive placental malaria [25ndash28] Earlier studies by Friedet al [18] reported elevated levels of T-helper-1 cytokinesin the placental plasma of placental malaria-positive womenincluding tumor necrosis factor alpha (TNF-120572) interferongamma (IFN-120574) and interleukin-2 (IL-2) Accordingly sev-eral studies have reported presence of T cells in the IVS ofwomen with placental malaria [28 29] Apart from cytokinesand chemokines secreted by maternal monocytes and T cellsstudies in chronic-infected placentas have implicated therole of B cells in placental inflammatory response duringplacental malaria [29 30] Therefore sequestration of IE inthe IVS and subsequent inflammation induces pathologicalchanges thatmay limit placental capacity to transfer nutrientsto the growing fetus therefore increasing risk of havingLBW babies The histopathological changes induced duringplacental malaria include ST degradation and destruction ofthe villous integrity [31] decrease in villous surface areas[32] fibrinoid necrosis [26 30] and thickening of trophoblastbasement membrane [26 30]

BioMed Research International 3

22 Response of Trophoblasts to Malaria In placenta infectedwith malaria ST are exposed to IE malaria pigment (hemo-zoin) maternal immune cells and inflammatory cytokinesStudies on response of ST to malaria have mostly been donein vitro Using primary trophoblasts and the BeWo cell lineLucchi et al [33 34] showed that binding of CSA-positivePlasmodium parasites to BeWo stimulated BeWo to secretecytokines including macrophage inhibitory factor (MIF)macrophage inhibitory protein- (MIP-) 1120572CCL3 (detected atthe protein level) and transforming growth factor- (TGF-) 120573(at the transcriptional level) In addition Lucchi et al alsodemonstrated that hemozoin could stimulate ST to secretechemokines CXCL8 CCL3 CCL4 and a cytokine TNF-120572as well as soluble intracellular adhesion molecule-1 (ICAM-1) [33] Furthermore data from the same group showed thatbinding of IE to ST induced phosphorylation of trophoblastsproteins [35] These studies suggest that ST respond to IEandnatural hemozoin by secreting cytokines and chemokinescommonly found in IVS of placentamalaria-positive womenMoreover the phosphorylation of trophoblast proteins fol-lowing IE binding implies that changes in the regulation ofprotein functions are induced However IE may produceother soluble and insoluble bioactive molecules to which STmight respond More studies identifying the response of STto IE bioactive molecules are needed

3 Placental Malaria andSyncytiotrophoblast Functions

31 Immunological Protection ST forms a physical barrierseparating maternal and fetal blood Under normal cir-cumstances ST also prevents hematogenous transmissionof infection from mother to the fetus including placental-P falciparum-IE The barrier has additional antimicrobialactivities synthesizing high levels of nitric oxide synthaseproducing microvillus-associated glycosaminoglycans andsecreting antiviral interferons [36] The fetal trophoblastscreate an immune-active barrier to pathogens Like innateimmune cells trophoblasts express pattern recognitionreceptors (PRR) including Toll-like receptors (TLR1-10) [37ndash39] and nucleotide-binding oligomerization domain (NOD)receptors including inflammasomes [40] While TLRs rec-ognize and respond to both extracellular and endosomalpathogen-associated molecular patterns (PAMPs) NOD re-ceptors are cytosolic sensors and therefore recognize intra-cellular PAMPs Studies on human trophoblasts have shownthat TLR expression on trophoblasts differs with gesta-tion age with certain types of TLRs being differentiallyexpressed in the first second or third trimesters (reviewedin [41]) This temporal expression of TLRs across ges-tation suggests that different responses are produced bytrophoblasts to various TLR ligands at different points ingestation For example TLR6 is only expressed by thirdtrimester trophoblasts and since TLR2 forms heterodimerswith either TLR1 or 6 upon stimulation TLR6 ligands maynot induce a response earlier in gestation Furthermorewhile TLR2TLR1 stimulation leads to apoptotic death inthe first trimester trophoblast the ligation of the same

ligand through TLR2TLR6 heterodimers prevents cell deathin human third trimester primary trophoblasts [42] As Pfalciparum has a number of well-characterized PAMPs suchas glycosylphosphatidylinositol- (GPI-) anchor which canactivateTLR2TLR1 andTLR2TLR6heterodimers (reviewedin [43]) the temporal expression of TLRs may explain thedifferential placental pathology observed during placentalmalaria throughout gestation This hypothesis is supportedby population based study in pregnant womenwhich demon-strated that having malaria infection in the first trimesterincreased the risk of miscarriage compared to having malariainfection in late gestation [44]

Other PAMPs associated with malaria include malarialhemozoin and parasite DNA Studies by Coban et al [16]established that the malarial hemozoin is a TLR9 ligandand it has since been proposed to activate the NLRP3inflammasome [17] Generally PRR-expression by the fetaltrophoblasts aids in combating pathogens in the IVS howeverthe resulting immune responses they induce may contributeto poor neonatal outcomes associated with sequestered par-asites during placental malaria Although TLRs are essentialinnate receptors at thematernal fetal interface the immediateresponse of ST to P falciparum-derived PAMPs cannotbe studied in vivo However the role of TLRs in somepathological pregnancies has been reported [45] Thereforethe question still remains Does ST response to Plasmodiumderived PAMPs via PRRs induce pathophysiological changesthat lead to FGR In other words do P falciparum-associatedPAMPs influence ST function

32 Transport and Metabolism Syncytiotrophoblast themajor transporting epithelium in the placenta is polarizedwith the ability for uptake and transfer of nutrients suchas amino acids glucose fatty acids minerals cholesteroland some xenobiotics The apical surface of ST is perfusedby maternal blood whereas the basal membrane is in inti-mate contact with fetal capillary networks The ST regu-lates maternal-fetal transport of nutrients including glucoseamino acids lipids gases and ions Owing to its syncytialnature transplacental transfer of nutrients for exampleamino acids and glucose is made possible by carrier proteinsthat are expressed on both apical and basal membranesof the ST Generally the driving force of the transport ofmost nutrients through ST depends on concentration and anelectrochemical gradient (eg glucose and ions) Howeveranother form of transport operates against the concentrationgradient of solutes and thus requires energy in terms ofhydrolysis of adenosine-51015840-triphosphate (ATP) Amino acidstransporters require energy in the form of ATP to transferamino acids from the apical surface to the basal membraneof ST [37]

Fetal growth is dependent upon the ST transportingactivities of various transporters Accordingly fetuses withrestricted growth often have low plasma concentrations ofamino acids and are hypoglycemic [46] This associationhas been reported by Jansson et al [47] who have shownthat the activities of several transporters are dysregulated in


pregnancies associated with idiopathic FGR including trans-porters for systemA amino acids (SLC38A) leucine sodium-dependent and -independent taurine Na+K+-ATPase Ca2+and Na+H+ exchanger Recently it was described that theSLC38A2 and SLC38A1 transcripts were downregulated inwomen with placental malaria with inflammation [48] sug-gesting that the uptake of amino acids by fetal cells is impairedduring placental malaria It should be noted that nutrientstaken up by the fetal ST influencemetabolism and subsequentnutrient delivery to the fetus The transfer of nutrients acrossST is influenced by the uteroplacental and umbilical bloodflow and regulated by various fetal maternal and placentalsignals [49] Several placental proteins placental signalingmolecules and placental hormones synthesized and secretedby the placenta facilitate transport of nutrients across ST(reviewed in [49]) influencing fetus growth

33 Regulation of Vasculogenesis and Angiogenesis Vasculo-genesis and angiogenesis are processes essential for creatingand maintaining uteroplacental blood flow and thereforeinfluence the exchange of nutrients between mother andfetus While angiogenesis refers to the formation of newblood vessels from preexisting ones vasculogenesis is theformation of blood vessels from endothelia cells The mainfactors produced by ST that regulate vasculogenesis andangiogenesis by fetal endothelia cells are vascular endothelialgrowth factors (VEGF) placental growth factor (PIGF) andtransforming growth factor (TGF) beta [50] VEGF signalsvia two specific receptors VEGFR-1 and VEGFR-2 by induc-ing the production of nitric oxide (NO) from trophoblastsThe literature suggests that VEGF PIGF and their respectivereceptors are important for regulating trophoblast survivaland angiogenesis [51] VEGF induces angiogenesis and reg-ulates vasculogenesis and therefore placental vasculatureOther molecules that perform angiogenic functions duringpregnancy are placental angiopoietins-1 (ANGPT-1 and -2)The ANGPTs are expressed by trophoblasts and induce theireffect via receptor kinases Tunica internal endothelial cellkinase-2 (Tie-2) receptor expressed on fetal endothelial cellsANGTP-Tie forms a vascular-specific ligandreceptor systemthat controls endothelia cell survival and vascularmaturationof placental and is therefore important for fetal growth(reviewed in [52])

Dysregulation of angiogenesis has been implicated inplacental-malaria-associated FGR from in vivo studies byDorman et al [53 54] and others [55] VEGF transcriptionlevels are reported to be lower in ST from placental malaria-positive-placentas as compared to ST from asymptomaticplacentas [56] In addition Neres et al [57] implicated vascu-logenesis impairment in pregnant P berghei-ANKA-positivemice Furthermore studies in the samemousemodel showeddysregulation of angiopoietins by placental malaria and thiscorrelated with FGR These animal studies are supported bycross-sectional and longitudinal studies in pregnant womenfrom endemic areas where the ANGPT-2 was elevated andANGPT-1 decreased in placental malaria-positive womenand correlated with having LBW babies [55 58] Otherstudies have shown that levels of antiangiogenic molecules

which are known to be produced by ST are elevated duringplacental malaria including the fms-like tyrosine kinase-1(sFLT1) a soluble vascular endothelia growth factor receptorthat sequesters VEGF-1 [59] and soluble endoglin [60]Previously genome wide expression studies using the BeWocell line [61] demonstrated that placental malaria-associatedcytokines dysregulated biological processes associated withplacental vasculogenesis and angiogenesis suggesting thatinflammatory response in the IVS during placental malariainterferes with blood flow a functional aspect of ST There-fore alterations in the production of angiogenic factors by STduring placentalmalaria could lead to poor vascularisation ofthe placenta and hence impair fetal growth

34 The Insulin-Like Growth Factor Signaling (IGF-1) AxisRegulation of Transplacental Transfer of Nutrients Cells Sur-vival and Proliferation The insulin-like growth factor (IGF)axis consists of two polypeptide hormones IGF-1 and IGF2 cell surface receptors IGF-1R and IGF-2R soluble IGF-binding proteins and an IGF-binding protease which all con-trol growth of many organs including the placenta Duringpregnancy the IGF are mainly secreted by the placental cellsincluding ST and the growing fetus IGF-1 is an importantgrowth pathway for regulation of placental and fetus growththroughout gestation it plays a major role in the transferof nutrients across the placenta through ST facilitating cellsurvival and proliferation [62 63] Gene-disruption studiesshow that mice carrying the IGF-1 mutant allele have a40 reduced birth weight In human mutation in the IGF-1 gene reduces fetus growth by 60 and subsequent postnatalgrowth [64] On the other hand IGF-R2 gene targeting inmice resulted in placental and fetus overgrowth [65] Inaddition Laviola et al [66] found a decrease in the expressionof IGF-1R and signaling molecules in human intrauterineFGR restricted-placentas These observations indicate thatimpairment of both IGF-I action through the absence ofIGF expression and IGF signaling molecules may lead toabnormal fetus and placental growth

Dysregulation of the IGF axis has been studied in LBWbabies and pathological pregnancies due to various causesChiesa et al [67] investigated the relationship betweenreduced maternal IGF-1 and FGR and found that IGF-1concentration was lower in pregnancies with FGR than innormal birth weight babies [67] In addition preeclampticpatients exhibit alterations of IGF binding protein-1 and IGF-2 at the fetus maternal interface [68] More recently it hasbeen shown that IGF-1 concentrations in the cord bloodof neonates born to placental malaria-positive mothers arelower than those born to mothers without placental malariaand these positively correlated with birth weight [68] Inthe referred study maternal IGF-1 concentration was posi-tively correlated with placental malaria with inflammationFurthermore in vitro studies by Kidima [61] using a pla-cental cell line (BeWo cells) showed that malaria-associatedcytokines and chemokines but not intact placental-binding-P falciparum IE dysregulated IGF1 pathway supporting theobservation by Umbers and group [68] Dysregulation of theIGF1 pathway during placental malaria may interfere with


the transfer of nutrients across the placenta and thereforeaffect fetal growth

35 The Mammalian Target for Rapamycin (mTOR) PathwayRegulator of Placental and Fetus Growth

351 The mTOR mTOR is a large serine threonine kinase(originally named as a target of rapamycin a bacteria toxinthat inactivated the kinase in yeast) which belongs to thephosphoinositide 3-kinase related kinase (PI3K) and is con-stitutively expressed in eukaryotic cells which function tocontrol growth (reviewed in [69]) [70 71] mTOR existsin two functional complexes mTOR complex 1 (mTORC1)which is sensitive to rapamycin and mTOR complex 2(mTORC2) which is not [72] mTOR functions to facilitateand promote cellular growth and metabolism in responseto diverse extracellular and intracellular signals [72 73] Forinstance the activities of mTORC1 are regulated by energystatus hormones growth factors amino acids glucose andoxygen [72 74] while those of mTORC2 can be activated bythe growth factors and amino acids

The mTOR signaling pathway regulates critical for cel-lular growth processes including protein and lipid synthe-sis regulation of cellular metabolism and ATP production(reviewed in [74]) angiogenesis (reviewed in [75]) andcytoskeleton organization [69] In addition mTOR controlscell survival by inhibiting apoptosis facilitating cell pro-liferation and actin organization and negatively regulatingautophagy Consequently mTOR is important in normalphysiological functioning of several tissues and cells [71] Itfollows therefore that dysregulation of the mTOR pathwayhas been reported to play a major role in several pathologicalevents including cancer metabolic diseases such as obe-sity and type two diabetes and neurodegenerative diseases(reviewed in [74])

352 Placental mTOR and Fetus Growth Placenta mTORis the regulator of placental and fetus growth PlacentalmTOR protein which is expressed in ST [76] is critical inregulating fetal growth by influencing transplacental trans-port of nutrients predominantly amino acids Evidences areshowing that growth factors hormones nutrients such asamino acids glucose [76ndash78] energy and stress [78] regulatethe placental mTOR activities just like in other cellstissuesStudies using human trophoblastic cells by Roos et al [79]reported that activation of amino acid transporting activitiesby the growth factors IGF-1 and insulin occurred throughthe mTOR signaling pathway Furthermore evidence showsthat mTOR stimulate expression and amino acid transportersin human placenta including system A and L as well astaurine transporters [79 80] and therefore enhance nutrientdelivery to the fetus ConsequentlymTOR signaling activitieswere reported to be reduced in FGR placentas [81] but themTOR protein expression increased suggesting occurrenceof adaptive response

Does Poor Maternal Nutrition Stir Placental Malaria Patho-genesis Is the Placental mTOR the Target The role of mTOR

in the pathogenesis of malaria is starting to unravel Forinstance it has been shown that inhibition ofmTOR signalingby treating Plasmodium berghei ANKA-infected mice withmTOR inhibitor rapamycin prevented pathology in an exper-imental cerebral malaria [82] Specifically the rapamycinPlasmodium berghei-positivemice had lower parasite densityless accumulation of IE in the brain and therefore no braindysfunction However the mTOR inhibitor failed to impedeinflammation Further research on the role of mTOR is nec-essary in placentalmalaria animalmodel such as the baboonwhere Plasmodium knowlesi have been shown to sequester tothe placenta [83] On the other hand in vitro studies usingthe BeWo cell line exposed to malaria-associated cytokinesplus chemokines (secreted by human monocytic cell line(THP1) cells that were incubated with P falciparum infectedred blood cells) induced dysregulation of mTOR pathway[61] suggesting thatmTORpathway in STmight be interferedby placental malaria-inflammatory-cytokines Furthermoreusing placental malaria-infected placentas Dimasuay et al[84] showed a dysregulation of mTOR in the placenta withchronic inflammation further supporting an observation thatplacental malaria with inflammation may deregulate themTOR pathway

However the placental mTOR links maternal nutrientavailability and fetus growth [76] Also the availability ofnutrients to the fetus entirely depends on the functional-placental growth pathways and hormones which signal to themTOR signaling pathway On the other hand the expressionof mTOR is influenced by nutrition such as amino acids[85] Interestingly many epidemiological studies in malariaendemic areas have implicated the association betweenmaternal nutrition and poor-neonatal outcome in womenwith placental malaria For example cohort studies by Landiset al [86] reported a 2- to 8-fold increase in risk of FGRin women with placental malaria that were undernourishedcompared to those who were well nourished Furthermorelongitudinal studies by Griffin et al [87] showed an increasein uterine artery resistance amongst the undernourishedwomen who had early-pregnancy-P falciparum-parasitemiacompared to those who had early parasitemia but were wellnourished suggesting placental insufficiencyThe increase inuterine resistance among placental malaria-positive womenwho were undernourished suggests that malaria may hamperthe adaptive responses which have been reported to occurin preeclamptic women or that had idiopathic FGR [88] Sothe question remains is the pathogenesis of placental malariathat leads to FGR stirred by lack of nutrients in the IVS ofplacenta And is placental mTOR the target

It follows therefore that since (i) nutrients activate themTOR pathway [89] and (ii) that mTOR links importantgrowth pathways IGF-1 VEGF and insulin pathways toregulate fetus growth in utero and (iii) that activation ofamino acid transporting activities by the growth factors IGF-1 and insulin occurred through themTOR signaling pathway[79] we hypothesize that lack of nutrients in the IVS duringpregnancy might stir up pathogenesis of placental malariaand hence FGR by downregulating the mTOR signalingpathway (Figure 2) It is therefore recommended that studies


IGF-1 and mTORsignaling pathways

Placental insufficiency

Fetus growth restriction

Amino acid uptake

Placental malaria

Placental vasculogenesis and angiogenesis

Nutrition

Figure 2 Model explaining biological mechanisms associatedwith the development of fetal growth restriction as a result ofplacental malaria Both in vivo and in vitro studies have documenteddysregulation of vasculogenesis and angiogenesis in placentalmalaria Moreover the IGF-1 and mTOR growth pathways that linkmaternal nutrients to fetal nutrient availability are downregulatedIn addition nutrient transporters particularly system A aminoacid transporters are downregulated during placental malaria andtherefore limit amino acid uptake Interestingly epidemiologicalstudies indicate nourishment or food availability during pregnancysignificantly override the effect of placental malaria on neonataloutcome (FGR) We hypothesize that supplementing pregnantwomen with allowable level of amino acids may override the effectof malaria on neonatal outcome (darr downregulate)

on potential interventional approach for placental malariaduring pregnancy should consider intermittently supple-menting placental malaria-high-risk-women with allowablelevels of essential amino acids and other micronutrients inmalaria endemic areas

4 Conclusion

Placenta malaria dysregulates aspects of ST functions whichassociate with delivering maternal nutrients to the fetus inutero therefore increasing the risk of FGR Establishing therole of placentamalaria on ST function aids in understandingthe pathophysiology induced by placental malaria and hasimplications in finding focus that could lead to the preventionof poor neonatal outcomes Nutrition may override theeffects of placental malaria on ST functions and thereforeimprove neonatal outcome during placental malariaThe roleof maternal nutrition in placental malaria pathogenesis hasan implication in future malaria interventional approaches

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

References

[1] H L Guyatt and R W Snow ldquoImpact of malaria duringpregnancy on low birth weight in Sub-Saharan Africardquo ClinicalMicrobiology Reviews vol 17 no 4 pp 760ndash769 2004

[2] M Militello E M Pappalardo S Ermito A Dinatale ACavaliere and S Carrara ldquoObstetric management of IUGRrdquoJournal of Prenatal Medicine vol 3 no 1 pp 6ndash9 2009

[3] R W Steketee B L Nahlen M E Parise and C MenendezldquoTheburden ofmalaria in pregnancy inmalaria-endemic areasrdquoTheAmerican Journal of Tropical Medicine and Hygiene vol 64supplement no 1-2 pp 28ndash35 2001

[4] D L Christensen A Kapur and I C Bygbjerg ldquoPhysiologicaladaption to maternal malaria and other adverse exposure lowbirthweight functional capacity and possiblemetabolic diseasein adult liferdquo International Journal of Gynecology and Obstetricsvol 115 supplement 1 pp S16ndashS19 2011

[5] J L Morrison J A Duffield B S Muhlhausler S Gentili and ICMcMillen ldquoFetal growth restriction catch-up growth and theearly origins of insulin resistance and visceral obesityrdquo PediatricNephrology vol 25 no 4 pp 669ndash677 2010

[6] B Gamain A R Trimnell C Scheidig A Schert L H Millerand J D Smith ldquoIdentification of multiple chondroitin sulfateA (CSA)-binding domains in the var2CSA gene transcribed inCSA-binding parasitesrdquo Journal of Infectious Diseases vol 191no 6 pp 1010ndash1013 2005

[7] J G Beeson S J Rogerson B M Cooke et al ldquoAdhesionof Plasmodium falciparum-infected erythrocytes to hyaluronicacid in placental malariardquoNature Medicine vol 6 no 1 pp 86ndash90 2000

[8] M Fried and P E Duffy ldquoAdherence of Plasmodium falciparumto chondroitin sulfate A in the human placentardquo Science vol272 no 5267 pp 1502ndash1504 1996

[9] J G Beeson S J Rogerson and G V Brown ldquoEvaluating spe-cific adhesion of Plasmodium falciparum-infected erythrocytesto immobilised hyaluronic acid with comparison to binding ofmammalian cellsrdquo International Journal for Parasitology vol 32no 10 pp 1245ndash1252 2002

[10] P Magistrado A Salanti N G Tuikue Ndam et al ldquoVAR2CSAexpression on the surface of placenta-derived Plasmodiumfalciparum-infected erythrocytesrdquo Journal of InfectiousDiseasesvol 198 no 7 pp 1071ndash1074 2008

[11] N K Viebig E Levin S Dechavanne et al ldquoDisruption ofVar2CSA gene impairs placental malaria associated adhesionphenotyperdquo PLoS ONE vol 2 no 9 article e910 2007

[12] A Salanti M Dahlback L Turner et al ldquoEvidence for theinvolvement of VAR2CSA in pregnancy-associated malariardquoJournal of Experimental Medicine vol 200 no 9 pp 1197ndash12032004

[13] M Fried G J Domingo C D Gowda T KMutabingwa and PE Duffy ldquoPlasmodium falciparum chondroitin sulfate A is themajor receptor for adhesion of parasitized erythrocytes in theplacentardquo Experimental Parasitology vol 113 no 1 pp 36ndash422006

[14] J Zhu G Krishnegowda G Li and D Channe GowdaldquoProinflammatory responses by glycosylphosphatidylinositols


(GPIs) of Plasmodium falciparum are mainly mediated throughthe recognition of TLR2TLR1rdquo Experimental Parasitology vol128 no 3 pp 205ndash211 2011

[15] P Parroche FN LauwNGoutagny et al ldquoMalaria hemozoin isimmunologically inert but radically enhances innate responsesby presenting malaria DNA to Toll-like receptor 9rdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 104 no 6 pp 1919ndash1924 2007

[16] C Coban Y Igari M Yagi et al ldquoImmunogenicity of whole-parasite vaccines against Plasmodium falciparum Involvesmalarial hemozoin and host TLR9rdquo Cell Host and Microbe vol7 no 1 pp 50ndash61 2010

[17] C Dostert G Guarda J F Romero et al ldquoMalarial hemozoinis a Nalp3 inflammasome activating danger signalrdquo PLoS ONEvol 4 no 8 article e6510 2009

[18] M Fried R O Muga A O Misore and P E Duffy ldquoMalariaelicits type 1 cytokines in the human placenta IFN-gamma andTNF-alpha associatedwith pregnancy outcomesrdquoThe Journal ofImmunology vol 160 no 5 pp 2523ndash2530 1998

[19] E T Abrams H Brown S W Chensue et al ldquoHost responseto malaria during pregnancy placental monocyte recruitmentis associated with elevated 120573 chemokine expressionrdquo Journal ofImmunology vol 170 no 5 pp 2759ndash2764 2003

[20] A L Suguitan Jr R G F Leke G Fouda et al ldquoChangesin the levels of chemokines and cytokines in the placentasof women with Plasmodium falciparum malariardquo Journal ofInfectious Diseases vol 188 no 7 pp 1074ndash1082 2003

[21] A L Suguitan Jr T J Cadigan T A Nguyen et al ldquoMalaria-associated cytokine changes in the placenta of women with pre-term deliveries in Yaounde Cameroonrdquo The American Journalof Tropical Medicine and Hygiene vol 69 no 6 pp 574ndash5812003

[22] S J Rogerson H C Brown E Pollina et al ldquoPlacental tumornecrosis factor alpha but not gamma interferon is associatedwith placental malaria and low birth weight in Malawianwomenrdquo Infection and Immunity vol 71 no 1 pp 267ndash2702003

[23] J N Bulmer F N Rasheed N Francis L Morrison and B MGreenwood ldquoPlacental malaria I Pathological classificationrdquoHistopathology vol 22 no 3 pp 211ndash218 1993

[24] C Menendez J Ordi M R Ismail et al ldquoThe impact ofplacental malaria on gestational age and birth weightrdquo TheJournal of Infectious Diseases vol 181 no 5 pp 1740ndash1745 2000

[25] P RWalter Y Garin and P Blot ldquoPlacental pathologic changesin malaria A histologic and ultrastructural studyrdquo AmericanJournal of Pathology vol 109 no 3 pp 330ndash342 1982

[26] M R Ismail J Ordi CMenendez et al ldquoPlacental pathology inmalaria a histological immunohistochemical and quantitativestudyrdquo Human Pathology vol 31 no 1 pp 85ndash93 2000

[27] S J Rogerson E Pollina A Getachew E Tadesse V MLema and M E Molyneux ldquoPlacental monocyte infiltrates inresponse to Plasmodium falciparummalaria infection and theirassociation with adverse pregnancy outcomesrdquo The AmericanJournal of Tropical Medicine and Hygiene vol 68 no 1 pp 115ndash119 2003

[28] E T Abrams H Brown S W Chensue et al ldquoHost response tomalaria during pregnancy placental monocyte recruitment isassociated with elevated 120573 chemokine expressionrdquo The Journalof Immunology vol 170 no 5 pp 2759ndash2764 2003

[29] J Ordi C Menendez M R Ismail et al ldquoPlacental malariais associated with cell-mediated inflammatory responses with

selective absence of natural killer cellsrdquo Journal of InfectiousDiseases vol 183 no 7 pp 1100ndash1107 2001

[30] J N Bulmer F N Rasheed L Morrison N Francis andB M Greenwood ldquoPlacental malaria II A semi-quantitativeinvestigation of the pathological featuresrdquo Histopathology vol22 no 3 pp 219ndash225 1993

[31] I P Crocker O M Tanner J E Myers J N Bulmer GWalraven and P N Baker ldquoSyncytiotrophoblast degradationand the pathophysiology of the malaria-infected placentardquoPlacenta vol 25 no 4 pp 273ndash282 2004

[32] S Chaikitgosiyakul M J Rijken A Muehlenbachs et alldquoA morphometric and histological study of placental malariashows significant changes to villous architecture in both Plas-modium falciparum and Plasmodium vivax infectionrdquo MalariaJournal vol 13 article 4 2014

[33] N W Lucchi D Sarr S O Owino S M Mwalimu D SPeterson and J M Moore ldquoNatural hemozoin stimulates syn-cytiotrophoblast to secrete chemokines and recruit peripheralblood mononuclear cellsrdquo Placenta vol 32 no 8 pp 579ndash5852011

[34] N W Lucchi D S Peterson and J M Moore ldquoImmunologicactivation of human syncytiotrophoblast by Plasmodium falci-parumrdquoMalaria Journal vol 7 article 42 2008

[35] N W Lucchi R Koopman D S Peterson and J M MooreldquoPlasmodium falciparum-infected red blood cells selected forbinding to cultured syncytiotrophoblast bind to chondroitinsulfate A and induce tyrosine phosphorylation in the syncy-tiotrophoblastrdquo Placenta vol 27 no 4-5 pp 384ndash394 2006

[36] G Aboagye-Mathiesen F D Tth P M Petersen and P Ebbe-sen ldquoHuman trophoblast interferons production purificationand biochemical characterizationrdquo Placenta vol 15 no 1 pp315ndash329 1994

[37] V M Abrahams and G Mor ldquoToll-like receptors and their rolein the trophoblastrdquo Placenta vol 26 no 7 pp 540ndash547 2005

[38] F Deng F Han and C Wu ldquoExpression and immune effectof toll-like receptor 4 in human trophoblast cellsrdquo Journal ofHuazhongUniversity of Science andTechnologyMedical Sciencevol 29 no 3 pp 359ndash362 2009

[39] S Komine-Aizawa H Majima C Yoshida-Noro and SHayakawa ldquoStimuli through Toll-like receptor (TLR) 3 and 9affect human chorionic gonadotropin (hCG) production in achoriocarcinoma cell linerdquo Journal of Obstetrics and Gynaecol-ogy Research vol 34 no 2 pp 144ndash151 2008

[40] M Mulla K Myrtolli J Potter et al ldquoUric acid induces tro-phoblast IL-1120573 production via the inflammasome implicationsfor the pathogenesis of preeclampsiardquo American Journal ofReproductive Immunology vol 65 no 6 pp 542ndash548 2015

[41] V M Abrahams ldquoPattern recognition at the maternal-fetalinterfacerdquo Immunological Investigations vol 37 no 5-6 pp 427ndash447 2008

[42] V M Abrahams P B Aldo S P Murphy et al ldquoTLR6 mod-ulates first trimester trophoblast responses to peptidoglycanrdquoJournal of Immunology vol 180 no 9 pp 6035ndash6043 2008

[43] R T Gazzinelli P Kalantari K A Fitzgerald and D T Golen-bock ldquoInnate sensing of malaria parasitesrdquo Nature ReviewsImmunology vol 14 no 11 pp 744ndash757 2014

[44] R McGready S J Lee J Wiladphaingern et al ldquoAdverse effectsof falciparum and vivax malaria and the safety of antimalarialtreatment in early pregnancy a population-based studyrdquo TheLancet Infectious Diseases vol 12 no 5 pp 388ndash396 2012


[45] P Chatterjee L EWeaver K M Doersch et al ldquoPlacental Toll-like receptor 3 and Toll-like receptor 78 activation contributesto preeclampsia in humans and micerdquo PLoS ONE vol 7 no 7Article ID e41884 9 pages 2012

[46] D L Economides and K H Nicolaides ldquoBlood glucoseand oxygen tension levels in small-for-gestational-age fetusesrdquoAmerican Journal of Obstetrics and Gynecology vol 160 no 2pp 385ndash389 1989

[47] T Jansson K Ylven M Wennergren and T L Powell ldquoGlu-cose transport and system A activity in syncytiotrophoblastmicrovillous and basal plasma membranes in intrauterinegrowth restrictionrdquo Placenta vol 23 no 5 pp 392ndash399 2002

[48] P Boeuf E H Aitken U Chandrasiri et al ldquoPlasmodium falci-parum malaria elicits inflammatory responses that dysregulateplacental amino acid transportrdquo PLoS Pathogens vol 9 no 2Article ID e1003153 2013

[49] S Lager and T L Powell ldquoRegulation of nutrient transportacross the placentardquo Journal of Pregnancy vol 2012 Article ID179827 14 pages 2012

[50] A S Cerdeira and S A Karumanchi ldquoAngiogenic factorsin preeclampsia and related disordersrdquo Cold Spring HarborPerspectives in Medicine vol 2 no 11 Article ID a006585 2012

[51] C E Powe R J Levine and S A Karumanchi ldquoPreeclampsia adisease of the maternal endothelium the role of antiangiogenicfactors and implications for later cardiovascular diseaserdquo Circu-lation vol 123 no 24 pp 2856ndash2869 2011

[52] D Kappou S Sifakis A Konstantinidou N Papantoniouand D A Spandidos ldquoRole of the angiopoietinTie system inpregnancy (Review)rdquo Experimental and Therapeutic Medicinevol 9 no 4 pp 1091ndash1096 2015

[53] E K Dorman C E Shulman J Kingdom et al ldquoImpaireduteroplacental blood flow in pregnancies complicated by falci-parum malariardquo Ultrasound in Obstetrics and Gynecology vol19 no 2 pp 165ndash170 2002

[54] T Todros A Sciarrone E Piccoli C Guiot P Kaufmannand J Kingdom ldquoUmbilical Doppler waveforms and placentalvillous angiogenesis in pregnancies complicated by fetal growthrestrictionrdquoObstetrics ampGynecology vol 93 no 4 pp 499ndash5031999

[55] A L Conroy K L Silver K Zhong et al ldquoComplement acti-vation and the resulting placental vascular insufficiency drivesfetal growth restriction associated with placental malariardquo CellHost and Microbe vol 13 no 2 pp 215ndash226 2013

[56] P Boeuf A Tan C Romagosa et al ldquoPlacental hypoxia duringplacental malariardquo Journal of Infectious Diseases vol 197 no 5pp 757ndash765 2008

[57] R Neres C R F Marinho L A Goncalves M B Catarino andC Penha-Goncalves ldquoPregnancy outcome and placenta pathol-ogy in Plasmodium berghei ANKA infected mice reproduce thepathogenesis of severe malaria in pregnant womenrdquo PLoS ONEvol 3 no 2 article e1608 2008

[58] K L Silver K Zhong R G F Leke DW Taylor andK C KainldquoDysregulation of angiopoietins is associated with placentalmalaria and low birth weightrdquo PLoS ONE vol 5 no 3 ArticleID e9481 2010

[59] AMuehlenbachs TKMutabingwa S EdmondsM Fried andP E Duffy ldquoHypertension and maternal-fetal conflict duringplacental malariardquo PLoS Medicine vol 3 no 11 article e4462006

[60] K L Silver A L Conroy R G F Leke et al ldquoCirculating solubleendoglin levels in pregnant women in Cameroon andMalawimdashassociationswith placentalmalaria and fetal growth restrictionrdquoPLoS ONE vol 6 no 9 Article ID e24985 2011

[61] W B Kidima Malaria associated changes in fetal syncytiotro-phoblast function [PhD dissertation] Department of TropicalMedicine Medical Microbiology and Pharmacology Universityof Hawaii at Manoa 2013

[62] A L Fowden ldquoThe insulin-like growth factors and feto-placental growthrdquo Placenta vol 24 no 8-9 pp 803ndash812 2003

[63] V E Murphy R Smith W B Giles and V L CliftonldquoEndocrine regulation of human fetal growth the role of themother placenta and fetusrdquo Endocrine Reviews vol 27 no 2pp 141ndash169 2006

[64] K A Woods C Camacho-Hubner M O Savage and A J LClark ldquoIntrauterine growth retardation and postnatal growthfailure associated with deletion of the insulin-like growth factorI generdquo The New England Journal of Medicine vol 335 no 18pp 1363ndash1367 1996

[65] MM H Lau C E H Stewart Z Liu H Bhatt P Rotwein andC L Stewart ldquoLoss of the imprinted IGF2cation-independentmannose 6-phosphate receptor results in fetal overgrowth andperinatal lethalityrdquo Genes amp Development vol 8 no 24 pp2953ndash2963 1994

[66] L Laviola S Perrini G Belsanti et al ldquoIntrauterine growthrestriction in humans is associated with abnormalities inplacental insulin-like growth factor signalingrdquo Endocrinologyvol 146 no 3 pp 1498ndash1505 2005

[67] C Chiesa J F Osborn C Haass et al ldquoGhrelin leptin IGF-1 IGFBP-3 and insulin concentrations at birth is there arelationship with fetal growth and neonatal anthropometryrdquoClinical Chemistry vol 54 no 3 pp 550ndash558 2008

[68] A J Umbers P Boeuf C Clapham et al ldquoPlacental malaria-associated inflammation disturbs the insulin-like growth factoraxis of fetal growth regulationrdquo Journal of Infectious Diseasesvol 203 no 4 pp 561ndash569 2011

[69] M Laplante and D M Sabatini ldquomTOR signaling at a glancerdquoJournal of Cell Science vol 122 no 20 pp 3589ndash3594 2009

[70] J Huang C C Dibble M Matsuzaki and B D Manning ldquoTheTSC1-TSC2 complex is required for proper activation of mTORcomplex 2rdquo Molecular and Cellular Biology vol 28 no 12 pp4104ndash4115 2008

[71] J D Powell K N Pollizzi E B Heikamp and M R HortonldquoRegulation of immune responses by mTORrdquoAnnual Review ofImmunology vol 30 pp 39ndash68 2012

[72] S Wullschleger R Loewith and M N Hall ldquoTOR signaling ingrowth andmetabolismrdquoCell vol 124 no 3 pp 471ndash484 2006

[73] D A Guertin and D M Sabatini ldquoDefining the role of mTORin cancerrdquo Cancer Cell vol 12 no 1 pp 9ndash22 2007

[74] M Laplante and D M Sabatini ldquoMTOR signaling in growthcontrol and diseaserdquo Cell vol 149 no 2 pp 274ndash293 2013

[75] Y Dobashi Y Watanabe C Miwa S Suzuki and S KoyamaldquoMammalian target of rapamycin a central node of complexsignaling cascadesrdquo International Journal of Clinical and Exper-imental Pathology vol 4 no 5 pp 476ndash495 2011

[76] S Roos T L Powell and T Jansson ldquoPlacental mTOR linksmaternal nutrient availability to fetal growthrdquo BiochemicalSociety Transactions vol 37 no 1 pp 295ndash298 2009

[77] S Roos O Lagerlof M Wennergren T L Powell and TJansson ldquoRegulation of amino acid transporters by glucoseand growth factors in cultured primary human trophoblast


cells is mediated by mTOR signalingrdquo American Journal ofPhysiologymdashCell Physiology vol 297 no 3 pp C723ndashC7312009

[78] C M Scifres and D M Nelson ldquoIntrauterine growth restric-tion human placental development and trophoblast cell deathrdquoJournal of Physiology vol 587 no 14 pp 3453ndash3458 2009

[79] S Roos Y Kanai P D Prasad T L Powell and T JanssonldquoRegulation of placental amino acid transporter activity bymammalian target of rapamycinrdquo American Journal of Physiol-ogy Cell Physiology vol 296 no 1 pp C142ndashC150 2009

[80] S Roos O Lagerlof M Wennergren T L Powell and TJansson ldquoRegulation of amino acid transporters by glucoseand growth factors in cultured primary human trophoblastcells is mediated by mTOR signalingrdquo The American Journalof PhysiologymdashCell Physiology vol 297 no 3 pp C723ndashC7312009

[81] S Roos N Jansson I Palmberg K Saljo T L Powell andT Jansson ldquoMammalian target of rapamycin in the humanplacenta regulates leucine transport and is down-regulated inrestricted fetal growthrdquo The Journal of Physiology vol 582 no1 pp 449ndash459 2007

[82] E B Gordon G T Hart T M Tran et al ldquoInhibiting theMammalian target of rapamycin blocks the development ofexperimental cerebralmalariardquomBio vol 6 no 3 pp 1ndash17 2015

[83] F I Onditi O W Nyamongo C O Omwandho et al ldquoParasiteaccumulation in placenta of non-immune baboons duringPlasmodium knowlesi infectionrdquoMalaria Journal vol 14 article118 2015

[84] G Dimasuay T Jansson J Glazier S Rogerson and P BoeufldquoPlacental mTOR signaling and fetal growth restriction inplacental malaria (132)rdquo in Proceedings of the Lorne Infectionand Immunity Conference Lorne Australia February 2014

[85] R Chen Y Zou D Mao et al ldquoThe general amino acidcontrol pathway regulates mTOR and autophagy duringserumglutamine starvationrdquo The Journal of Cell Biology vol206 no 2 pp 173ndash182 2014

[86] S H Landis V Lokomba C V Ananth et al ldquoImpact ofmaternal malaria and under-nutrition on intrauterine growthrestriction a prospective ultrasound study in DemocraticRepublic of Congordquo Epidemiology amp Infection vol 137 no 2 pp294ndash304 2009

[87] J B Griffin V Lokomba S H Landis et al ldquoPlasmodium fal-ciparum parasitaemia in the first half of pregnancy uterine andumbilical artery blood flow and foetal growth a longitudinalDoppler ultrasound studyrdquoMalaria Journal vol 11 no 1 article319 2012

[88] Y Aiko D J Askew S Aramaki et al ldquoDifferential levels ofamino acid transporters system L and ASCT2 and the mTORprotein in placenta of preeclampsia and IUGRrdquoBMCPregnancyand Childbirth vol 14 no 1 article 181 12 pages 2014


Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Maternal tissue

MQ M

Lymphocyte

GP1-anchor

TLR12

DNA

Hemozoin

VAR2CSA

HA

IE

CSA (a)

(b) (c)

E

IVS

Syncytiotrophoblast

Chemokine(s) Cytokine(s)

Cytokine R NALP3 TLR9

Figure 1 The microenvironment in the intervillous space of the placenta during active placental malaria (a) Interaction of parasite ligandVAR2CSA [10 12] with CSA that is expressed by ST [8 13] (b) Recognition of parasite bioactive molecules of schizogony by surface PRRsexpressed by both maternal macrophages and fetal syncytiotrophoblast that is malarial GPI-anchor bind TLR1TLR2 or TLR2TLR6 [14]and parasitersquos DNA is recognized by TLR9 [15] and hemozoin by TLR9 (see [16] and inflammasome (NALP3) [17]) (c) Inflammation in theIVS is attributed to chemokines and cytokines secreted by maternal macrophages monocytes and T cell as well as ST [15 16 18ndash20] (HAhyaluronic acid CSA chondroitin sulphate A IVS intervillous space NALP3 inflammasome GPI glycosylphosphatidylinositol IE infectederythrocyte E erythrocyte)

Generally sequestration of IE in the IVS leads to secretion ofchemokines resulting in inflammatory cells recruitment andcytokine productionwhich is associatedwith poor pregnancyoutcomes [18 21 22] Although placental malaria is largelyasymptomatic there is a correlation between peripheral andplacental parasitemia at delivery Placental malaria can becategorized as acute chronic or previous infection usingspecific pathological criteria [23] While chronic placentalmalaria has been associated with an increased risk of FGRacute placental malaria has been associated with PTD inmalaria endemic areas [24] However the major questions todate are the mechanisms on how chronic placental malariainduces FGR and PTD In this review we discuss selectedfunctions of ST and then highlight the role of malaria indysregulation of these functions using evidence from animalhuman and in vitro studies We then develop a modelthat describes the relationship between placental malariaFGR and the dysregulated syncytiotrophoblast function Wesuggest a potential interventional approach targeting STusing evidence from epidemiological studies

2 The Placenta and Its Response to Malaria

21 Maternal Responses to Malaria and Effect on the PlacentaAlthough pathogenesis of placental malaria is not completely

understood the IE binding to ST and recognition of parasiteby maternal macrophages induce secretion of chemokinesthat recruit maternal monocytes into the IVS resulting ininflammation Studies show that there is high level of mono-cytes and macrophages in the IVS of the placenta duringactive placental malaria [25ndash28] Earlier studies by Friedet al [18] reported elevated levels of T-helper-1 cytokinesin the placental plasma of placental malaria-positive womenincluding tumor necrosis factor alpha (TNF-120572) interferongamma (IFN-120574) and interleukin-2 (IL-2) Accordingly sev-eral studies have reported presence of T cells in the IVS ofwomen with placental malaria [28 29] Apart from cytokinesand chemokines secreted by maternal monocytes and T cellsstudies in chronic-infected placentas have implicated therole of B cells in placental inflammatory response duringplacental malaria [29 30] Therefore sequestration of IE inthe IVS and subsequent inflammation induces pathologicalchanges thatmay limit placental capacity to transfer nutrientsto the growing fetus therefore increasing risk of havingLBW babies The histopathological changes induced duringplacental malaria include ST degradation and destruction ofthe villous integrity [31] decrease in villous surface areas[32] fibrinoid necrosis [26 30] and thickening of trophoblastbasement membrane [26 30]






























Amino acid uptake

Placental malaria


Nutrition



4 Conclusion




References







































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






























Amino acid uptake

Placental malaria


Nutrition



4 Conclusion




References







































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






















Amino acid uptake

Placental malaria


Nutrition



4 Conclusion




References







































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology















Amino acid uptake

Placental malaria


Nutrition



4 Conclusion




References







































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





Amino acid uptake

Placental malaria


Nutrition



4 Conclusion




References







































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

























































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology
























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






















Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Documents

Review Article Syncytiotrophoblast Functions and Fetal ...malaria on syncytiotrophoblast function is paramount in developing novel interventions for the control of placental pathology